rs922736614

chr17-7676399-G-Achr17-7676399-G-Cchr17-7676399-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000546.6(TP53):c.79C>T(p.Pro27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P27T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 2.45

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 12 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.79C>T	p.Pro27Ser	missense_variant	3/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.79C>T	p.Pro27Ser	missense_variant	3/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249602 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135610

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461666 Hom.: 0 Cov.: 47 AF XY: 0.00000138 AC XY: 1 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 10, 2022	The p.P27S variant (also known as c.79C>T), located in coding exon 2 of the TP53 gene, results from a C to T substitution at nucleotide position 79. The proline at codon 27 is replaced by serine, an amino acid with similar properties. This variant is reported to have functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has no dominant negative effect (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Li-Fraumeni syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 27, 2021

This sequence change has not been previously described in patients with TP53-related disorders and has been described in the gnomAD database with a low population frequency of 0.00080% (dbSNP rs922736614). The p.Pro27Ser change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro27Ser substitution. Functional assays have shown that this sequence change does not have an impact on transcriptional transactivation activity of the TP53 protein (PMID: 12826609). Experimental studies showed that this sequence change exhibits high binding affinity of the TP53 protein to its partner protein MDM2 which may lead to a conformational change (PMID: 21528875). Due to these contrasting evidences, the clinical significance of the p.Pro27Ser change remains unknown at this time. -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 528271). This variant has not been reported in the literature in individuals affected with TP53-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 27 of the TP53 protein (p.Pro27Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.025	T;T;D;.;.;.;D;.;T;T;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T;.;T;T;.;T;D;D;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.99	D;D;D;D;D;D
PROVEAN	Benign	-1.1	N;N;N;.;N;N;N;.;N;N;.;D
REVEL	Uncertain	0.62
Sift	Benign	0.064	T;T;D;.;T;D;D;.;D;D;.;D
Sift4G	Benign	0.084	T;T;T;T;T;T;T;T;.;.;D;.
Polyphen		0.79	P;.;B;B;D;B;B;.;P;P;.;.
Vest4		0.49
MutPred		0.52		Gain of phosphorylation at P27 (P = 0.0797);Gain of phosphorylation at P27 (P = 0.0797);Gain of phosphorylation at P27 (P = 0.0797);Gain of phosphorylation at P27 (P = 0.0797);Gain of phosphorylation at P27 (P = 0.0797);Gain of phosphorylation at P27 (P = 0.0797);Gain of phosphorylation at P27 (P = 0.0797);Gain of phosphorylation at P27 (P = 0.0797);Gain of phosphorylation at P27 (P = 0.0797);Gain of phosphorylation at P27 (P = 0.0797);Gain of phosphorylation at P27 (P = 0.0797);Gain of phosphorylation at P27 (P = 0.0797);
MVP		0.92
MPC		0.85
ClinPred		0.37	T
GERP RS		3.9
Varity_R		0.25
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs922736614; hg19: chr17-7579717; COSMIC: COSV52696702; COSMIC: COSV52696702;